Osteoporosis describes a group of diseases which arises from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate support for the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal women.
There are an estimated 25 million women in the United States alone who are afflicted with this disease. The results of osteoporosis are personally harmful, and also account for a large economic loss due to its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is generally not thought of as a life threatening condition, a 20% to 30% mortality rate is related to hip fracturers in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of postmenopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which interconnect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This interconnected network of trabeculae gives lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall structure. In postmenopausal osteoporosis, it is primarily the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in the postmenopausal woman, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, for example, the vertebrae, the neck of the weight-bearing bones such as the femur and the forearm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hallmarks of postmenopausal osteoporosis.
The most generally accepted method for the treatment of postmenopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low, primarily because estrogen treatment frequently produces undesirable side effects. An additional method of treatment would be the administration of a bisphosphonate compound, such as, for example, Fosamax(copyright) (Merck and Co., Inc.).
Throughout premenopausal time, most women have less incidence of cardiovascular:disease than men of the same age. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can up regulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally,liestrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that serum lipid levels in postmenopausal women having estrogen replacement therapy return to concentrations found in the premenopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which regulates serum lipid levels in a manner analogous to estrogen, but which is devoid of the side, effects and risks associated with estrogen therapy.
A number of structurally unrelated compounds are capable of interacting with the estrogen receptor and producing unique in vivo profiles. Compounds with in vivo profiles typical of a xe2x80x9cpurexe2x80x9d antagonist (for example, ICI 164,384) or of a relatively xe2x80x9cpurexe2x80x9d agonist (for example, 17xcex2-estradiol) represent opposite ends of a spectrum in this classification. Between these two extremes lie the SERMs (xe2x80x9cselective estrogen receptor modulatorxe2x80x9d), characterized by clinical and/or preclinical selectivity as full or partial agonists in certain desired tissues (for example, bone), and antagonists or minimal agonists in reproductive tissues. Within this pharmacologic class, individual SERMs may be further differentiated based on profiles of activity in reproductive tissues. Raloxifene, a second generation SERM, displays potentially useful selectivity in uterine tissue with apparent advantages over triphenylethylene-based estrogen receptor ligands. As such, raloxifene appears to be well-suited at least for the treatment of postmenopausal complications, including osteoporosis and cardiovascular disease. It is anticipated that, as further advances are made in the pharmacology and molecular biology of estrogen receptor active agents, further subclassifications of SERMs may evolve in the future along with an increased understanding of the therapeutic utility of these novel classes of estrogenic compounds.
The advancement of raloxifene, in particular, has been somewhat hampered by its physical characteristics, both as to bioavailability and manufacturing. For example, raloxifene is generally insoluble, which may affect bioavailability. Clearly, any improvement in the physical characteristics of raloxifene and in closely related compounds would potentially offer a more beneficial therapy and enhanced manufacturing capabilities.
Thus, it would be a significant contribution to the art to provide amorphous forms of raloxifene and related compounds which have increased solubility, methods of preparation, pharmaceutical formulations, and methods of use.
The present invention provides a compound of formula I 
wherein:
R1 and R3 are independently hydrogen, xe2x80x94CH3, xe2x80x94CO(C1-C6 alkyl), or xe2x80x94COAr, wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidinyl, hexamethyleneimino, and piperidinyl; or a pharmaceutically acceptable salt or solvate thereof, in an amorphous form.